title: EZH2 in normal and malignant hematopoiesis.
abstract: The histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), a component of the polycomb group complex, is vital for stem cell development, including hematopoiesis. Its primary function, to deposit the histone mark H3K27me3, promotes transcriptional repression. The activity of EZH2 influences cell fate regulation, namely the balance between self-renewal and differentiation. The contribution of aberrant EZH2 expression to tumorigenesis by directing cells toward a cancer stem cell (CSC) state is increasingly recognized. However, its role in hematological malignancies is complex. Point mutations, resulting in gain-of-function, and inactivating mutations, reported in lymphoma and leukemia, respectively, suggest that EZH2 may serve a dual purpose as an oncogene and tumor-suppressor gene. The reduction of CSC self-renewal via EZH2 inhibition offers a potentially attractive therapeutic approach to counter the aberrant activation found in lymphoma and leukemia. The discovery of small molecules that specifically inhibit EZH2 raises the exciting possibility of exploiting the oncogenic addiction of tumor cells toward this protein. However, interference with the tumor-suppressor role of wild-type EZH2 must be avoided. This review examines the role of EZH2 in normal and malignant hematopoiesis and recent developments in harnessing the therapeutic potential of EZH2 inhibition.
authors.affiliation: Department of Epigenetics of Cancer and Aging, Institute of Cancer Sciences, University of Glasgow, Cancer Research UK Beatson Labs, Glasgow, Scotland, UK.
authors.forename: K
authors.initials: K
authors.lastname: Lund
authors.affiliation: Department of Epigenetics of Cancer and Aging, Institute of Cancer Sciences, University of Glasgow, Beatson Institute for Cancer Research, Glasgow, Scotland, UK.
authors.forename: P D
authors.initials: PD
authors.lastname: Adams
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow, Scotland.
authors.forename: M
authors.initials: M
authors.lastname: Copland
mesh_terms: D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D019337:Hematologic Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D017354:Point Mutation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism
chemical_list: C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2